Systems and methods for using electrical impedance for neuro cardiac therapy

ABSTRACT

A device embodiment is configured to deliver vagal stimulation therapy (VST) to a vagus nerve of a patient. The device embodiment includes a neural stimulator, an implantable impedance sensor and an impedance analyzer. The neural stimulator is configured to deliver the VST to the vagus nerve in a cervical region of the patient. The implantable impedance sensor is configured to detect impedance changes in a cervical region of the patient caused by laryngeal vibrations. The impedance sensor is configured to generate sensed impedance values. The impedance analyzer is configured to analyze the sensed impedance values generated by the sensor. The analyzer is configured to detect laryngeal vibrations or cough from the sensed impedance values.

CLAIM OF PRIORITY

This application claims the benefit of priority under 35 U.S.C. §119(e)of Arcot-Krishnamurthy et al., U.S. Provisional Patent Application Ser.No. 61/427,978, entitled “SYSTEMS AND METHODS FOR USING ELECTRICALIMPEDANCE FOR NEURO CARDIAC THERAPY”, filed on Dec. 29, 2010, which isherein incorporated by reference in its entirety.

TECHNICAL FIELD

This application relates generally to medical devices and, moreparticularly, to systems, devices and methods for delivering neuralstimulation.

BACKGROUND

Neural stimulation, such as vagus nerve stimulation, has been proposedas a therapy for a number of conditions. Examples of neural stimulationtherapies include neural stimulation therapies for respiratory problemssuch as sleep disordered breathing, blood pressure control such as totreat hypertension, cardiac rhythm management, myocardial infarction andischemia, heart failure (HF), epilepsy, depression, pain, migraines,eating disorders and obesity, and movement disorders.

SUMMARY

According to an embodiment of a method for detecting laryngealvibrations, impedance in a cervical region of a patient is sensed tosense changes in impedance characteristics caused by laryngealvibrations. Sensing impedance includes sensing impedance a plurality oftimes to provide a plurality of sensed impedance values. The pluralityof the sensed impedance values is analyzed to confirm the laryngealvibrations.

According to an embodiment of a method for detecting cough, impedance ina cervical region of a patient is sensed to sense changes in impedancecharacteristics caused by cough. Sensing impedance includes sensingimpedance a plurality of times to provide a plurality of sensedimpedance values. The plurality of the sensed impedance values isanalyzed to confirm the cough.

An embodiment of a method includes delivering a vagal stimulationtherapy (VST) to the vagus nerve of a patient, and detecting laryngealvibrations to determine whether the VST is capturing the vagus nerve.Detecting laryngeal vibrations includes sensing impedance in a cervicalregion of a patient to sense changes in impedance characteristics causedby laryngeal vibrations wherein sensing impedance includes sensingimpedance a plurality of times to provide a plurality of sensedimpedance values, and analyzing a plurality of the sensed impedancevalues to confirm the laryngeal vibrations. The values may be analyzedeither by itself or by comparison with baseline impedance valuescollected without any VST.

An embodiment of a method includes performing a threshold determinationroutine for delivering a vagal stimulation therapy (VST) to a vagusnerve of a patient. Performing the threshold determination routineincludes delivering VST to the vagus nerve, changing (increasing ordecreasing) an intensity of the VST in a plurality of intensity steps,and at each intensity step monitoring for laryngeal vibrations.Monitoring for laryngeal vibrations includes sensing impedance in acervical region of a patient to sense impedance changes caused bylaryngeal vibrations wherein sensing impedance includes sensingimpedance a plurality of times to provide a plurality of sensedimpedance values, and analyzing a plurality of the sensed impedancevalues to confirm the laryngeal vibrations.

A device embodiment is configured to deliver vagal stimulation therapy(VST) to the vagus nerve of a patient. The device embodiment includes aneural stimulator, an implantable impedance sensor and an impedanceanalyzer. The neural stimulator is configured to deliver the VST to thevagus nerve in the cervical region of the patient. The implantableimpedance sensor is configured for use in detecting changes in impedancecharacteristics in the cervical region of the patient caused bylaryngeal vibrations. The impedance sensor is configured to generatesensed impedance values. The impedance analyzer is configured to analyzethe sensed impedance values generated by the sensor. The analyzer isconfigured to detect laryngeal vibrations or cough from the sensedimpedance values.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Thescope of the present invention is defined by the appended claims andtheir equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments are illustrated by way of example in the figures ofthe accompanying drawings. Such embodiments are demonstrative and notintended to be exhaustive or exclusive embodiments of the presentsubject matter.

FIG. 1 illustrates intensity thresholds that elicit variousphysiological responses to VST.

FIG. 2 illustrates au intensity threshold that elicits an undesiredphysiological response to VST that is used to define an upper boundaryfor the VST intensity and another intensity threshold that elicitsanother physiological response to VST, according to various embodiments.

FIG. 3 illustrates that a VST intensity level can be set using theintensity threshold that elicits a physiological response to the VST,according to various embodiments.

FIG. 4 illustrates using the intensity threshold that elicits aphysiological response to set upper and lower limits for a range of VSTintensities, according to various embodiments.

FIG. 5 illustrates the intensity threshold that elicits a physiologicalresponse to the VST that is used to set the VST intensity, according tovarious embodiments.

FIG. 6 illustrates using a detected cough response to VST to limitadjustments to the VST intensity range, according to variousembodiments.

FIG. 7 illustrates an embodiment, by way of example and not limitation,of an implantable medical device capable of measuring impedance with adevice housing or can and a lead extending from the can.

FIG. 8 illustrates a representation of intermittent neural stimulation(INS), according to various embodiments.

FIG. 9 illustrates a memory, according to various embodiments, thatincludes instructions, operable on by the stimulation control circuitry,for controlling an up-titration routine by progressively stepping upthrough defined parameter sets (e.g. parameter set 1 through parameterset N), where each set incrementally increases the stimulation dose orintensity of the stimulation therapy.

FIG. 10 illustrates an embodiment of a therapy titration module.

FIG. 11 illustrates an embodiment of a routine that increases theintensity of the NCT therapy over a period of time.

FIGS. 12A and 12B illustrate, by way of example, impedance measurementssuch as may be sensed according to the present subject matter.

FIG. 13A illustrates the frequency transformation of the vagalstimulation pulses delivered at 160 beats per minute where the two peaksin frequencies are at 2.6 and 5.2 Hz respectively; and FIG. 13 Billustrates the frequency transformation of the impedance signalcollected during the vagal stimulation where the two primary peaks areagain at 2.6 Hz and 5.2 Hz, thus verifying capture by corresponding tothe peak frequencies of the vagal stimulation pulses.

FIG. 14 illustrates a step up in the variability of the sensed impedancewhen laryngeal vibrations occur and

FIG. 15 illustrates a step up in the variability of the sensed impedancewhen cough occurs, which are detected according to various embodimentsof the present subject matter.

FIG. 16 illustrates a VST system, according to various embodiments.

FIG. 17 illustrates an implantable medical device (IMD) having a neuralstimulation (NS) component and a cardiac rhythm management (CRM)component according to various embodiments of the present subjectmatter.

FIG. 18 shows a system diagram of an embodiment of amicroprocessor-based implantable device, according to variousembodiments.

FIG. 19 illustrates a system embodiment in which an IMD is placedsubcutaneously or submuscularly in a patient's chest with lead(s)positioned to stimulate a vagus nerve.

FIG. 20 illustrates an IMD placed subcutaneously or submuscularly in apatient's chest with lead(s) positioned to provide a CRM therapy to aheart, and with lead(s) positioned to stimulate and/or inhibit neuraltraffic at a neural target, such as a vagus nerve, according to variousembodiments.

FIG. 21 is a block diagram illustrating an embodiment of an externalsystem.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. References to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.The following detailed description is, therefore, not to be taken in alimiting sense, and the scope is defined only by the appended claims,along with the full scope of legal equivalents to which such claims areentitled.

The autonomic nervous system (ANS) regulates “involuntary” organs, whilethe contraction of voluntary (skeletal) muscles is controlled by somaticmotor nerves. Examples of involuntary organs include respiratory anddigestive organs, and also include blood vessels and the heart. Often,the ANS functions in an involuntary, reflexive manner to regulateglands, to regulate muscles in the skin, eye, stomach, intestines andbladder, and to regulate cardiac muscle and the muscles around bloodvessels, for example.

The ANS includes the sympathetic nervous system and the parasympatheticnervous system. The sympathetic nervous system is affiliated with stressand the “fight or flight response” to emergencies. Among other effects,the “fight or flight response” increases blood pressure and heart rateto increase skeletal muscle blood flow, and decreases digestion toprovide the energy for “fighting or fleeing.” The parasympatheticnervous system is affiliated with relaxation and the “rest and digestresponse” which, among other effects, decreases blood pressure and heartrate, and increases digestion to conserve energy. The ANS maintainsnormal internal function and works with the somatic nervous system.Afferent nerves convey impulses toward a nerve center, and efferentnerves convey impulses away from a nerve center.

Stimulating the sympathetic and parasympathetic nervous systems cancause heart rate, blood pressure and other physiological responses. Forexample, stimulating the sympathetic nervous system dilates the pupil,reduces saliva and mucus production, relaxes the bronchial muscle,reduces the successive waves of involuntary contraction (peristalsis) ofthe stomach and the motility of the stomach, increases the conversion ofglycogen to glucose by the liver, decreases urine secretion by thekidneys, and relaxes the wall and closes the sphincter of the bladder.Stimulating the parasympathetic nervous system (inhibiting thesympathetic nervous system) constricts the pupil, increases saliva andmucus production, contracts the bronchial muscle, increases secretionsand motility in the stomach and large intestine, and increases digestionin the small intestine, increases urine secretion, and contracts thewall and relaxes the sphincter of the bladder. The functions associatedwith the sympathetic and parasympathetic nervous systems are many andcan be complexly integrated with each other.

A reduction in parasympathetic nerve activity contributes to thedevelopment and progression of a variety of cardiovascular diseases.Some embodiments of the present subject matter can be used toprophylactically or therapeutically treat various cardiovasculardiseases by modulating autonomic tone. Neural stimulation to treatcardiovascular diseases is referred to herein as neuro cardiac therapy(NCT). Vagal stimulation used to treat cardiovascular diseases may betermed either VST or NCT. However, VST may be delivered fornon-cardiovascular diseases, and NCT may be delivered by stimulating anerve other than the vagal nerve. Examples of cardiovascular diseases orconditions include HF, hypertension, and cardiac remodeling. Theseconditions are briefly described below.

HF refers to a clinical syndrome in which cardiac function causes abelow normal cardiac output that can fall below a level adequate to meetthe metabolic demand of peripheral tissues. HF may present itself ascongestive heart failure (CHF) due to the accompanying venous andpulmonary congestion. HF can be due to a variety of etiologies such asischemic heart disease. HF patients have impaired autonomic balance,which is associated with LV dysfunction and increased mortality.

Hypertension is a cause of heart disease and other related cardiacco-morbidities. Hypertension occurs when blood vessels constrict. As aresult, the heart works harder to maintain flow at a higher bloodpressure, which can contribute to HF. Hypertension generally relates tohigh blood pressure, such as a transitory or sustained elevation ofsystemic arterial blood pressure to a level that is likely to inducecardiovascular damage or other adverse consequences. Hypertension hasbeen defined as a systolic blood pressure above 140 mm Hg or a diastolicblood pressure above 90 mm Hg. Consequences of uncontrolled hypertensioninclude, but are not limited to, retinal vascular disease and stroke,left ventricular hypertrophy and failure, myocardial infarction,dissecting aneurysm, and renovascular disease. A large segment of thegeneral population, as well as a large segment of patients implantedwith pacemakers or defibrillators, suffer from hypertension. The longterm mortality as well as the quality of life can be improved for thispopulation if blood pressure and hypertension can be reduced. Manypatients who suffer from hypertension do not respond to treatment, suchas treatments related to lifestyle changes and hypertension drugs.

Cardiac remodeling refers to a complex remodeling process of theventricles that involves structural, biochemical, neurohormonal, andelectrophysiologic factors, which can result following a myocardialinfarction (MI) or other cause of decreased cardiac output. Ventricularremodeling is triggered by a physiological compensatory mechanism thatacts to increase cardiac output due to so-called backward failure whichincreases the diastolic filling pressure of the ventricles and therebyincreases the so-called preload (i.e., the degree to which theventricles are stretched by the volume of blood in the ventricles at theend of diastole). An increase in preload causes an increase in strokevolume during systole, a phenomena known as the Frank-Starlingprinciple. When the ventricles are stretched due to the increasedpreload over a period of time, however, the ventricles become dilated.The enlargement of the ventricular volume causes increased ventricularwall stress at a given systolic pressure. Along with the increasedpressure-volume work done by the ventricle, this acts as a stimulus forhypertrophy of the ventricular myocardium. The disadvantage ofdilatation is the extra workload imposed on normal, residual myocardiumand the increase in wall tension (Laplace's Law) which represent thestimulus for hypertrophy. If hypertrophy is not adequate to matchincreased tension, a vicious cycle ensues which causes further andprogressive dilatation. As the heart begins to dilate, afferentbaroreceptor and cardiopulmonary receptor signals are sent to thevasomotor central nervous system control center, which responds withhormonal secretion and sympathetic discharge. The combination ofhemodynamic, sympathetic nervous system and hormonal alterations (suchas presence or absence of angiotensin converting enzyme (ACE) activity)account for the deleterious alterations in cell structure involved inventricular remodeling. The sustained stresses causing hypertrophyinduce apoptosis (i.e., programmed cell death) of cardiac muscle cellsand eventual wall thinning which causes further deterioration in cardiacfunction. Thus, although ventricular dilation and hypertrophy may atfirst be compensatory and increase cardiac output, the processesultimately result in both systolic and diastolic dysfunction. It hasbeen shown that the extent of ventricular remodeling is positivelycorrelated with increased mortality in post-MI and heart failurepatients.

The vagus nerve is a complex physiological structure with many neuralpathways that are recruited at different stimulation thresholds. Variousphysiological responses to vagal stimulation are associated with variousthresholds of VST intensity. For example, FIG. 1 illustrates increasingVST intensity from the left side to the right side of the figure, andfurther illustrates intensity thresholds that elicit variousphysiological responses to VST. VST causes a physiological response “A”at a lower intensity than an intensity at which VST causes aphysiological response “B”, which occurs at a lower VST intensity thanan intensity at which VST causes a physiological response “C”. Statedanother way, VST has to reach a certain level before triggering response“A,” and has to reach a higher intensity to trigger response “B” alongwith response “A” and an even higher intensity to trigger response “C”along with responses “A” and “B”.

The beneficial effects of VST on cardiac function and remodeling are notnecessarily mediated via heart rate reduction. That is, VST can benefitpatients without undesired chronotropic effects associated with VST aswell as other side effects due to high intensity stimulation such ascoughing, muscle stimulation, etc. Rather, anti-inflammatory,anti-sympathetic, and anti-apoptosis mediators are triggered at lowerVST intensities than intensities at which a heart rate reduction isrealized. These mediators function as pathways through which the VSTprovides the therapeutic effects for cardiovascular disease.

Physiological responses at the lower VST intensities havetherapeutically-effective results for cardiovascular diseases such asHF. These responses mediate or provide pathways for these therapies.Examples of such responses that are beneficial for HF at the lower VSTintensities include anti-inflammation, anti-sympathetic, andanti-apoptosis responses, and an increased nitric oxide (NO).Physiological responses at the higher VST intensities may not bedesirable. Examples of responses to higher VST intensities that mayreduce the ability of the patient to tolerate VST include, but are notlimited to, reduced heart rate, prolonged AV conduction, vasodilation,and coughing. At least some of these responses may be desirable for sometherapies but not desirable for other therapies. By way of example andnot limitation, VST that reduces heart rate and or that prolongs AVconduction may be desirable to treat some cardiovascular diseases, butmay not be desirable for other cardiovascular diseases. The intensity ofthe VST can be adjusted by adjusting parameter(s) of the stimulationsignal. For example, the amplitude of the signal (e.g. current orvoltage) can be increased to increase the intensity of the signal. Otherstimulation parameter(s) can be adjusted as an alternative to or inaddition to amplitude. For example, stimulation intensity can vary withthe frequency of the stimulation signal, a stimulation burst frequency,a pulse width and/or a duty cycle.

FIG. 2 illustrates increasing VST intensity from the left side to theright side of the figure, and further illustrates an intensity thresholdthat elicits an undesired physiological response to VST that is used todefine an upper boundary for the VST intensity and another intensitythreshold that elicits another physiological response to VST. Forexample, the VST intensity threshold for a cough can be used as an upperboundary, and the VST intensity threshold for a laryngeal vibrationresponse can be used as a lower boundary. In some embodiments, thephysiological response to define the upper boundary is a detected musclestimulation. Large muscle stimulation or extraneous stimulation may bebothersome to the patient. Various embodiments use lead impedance tocheck for vagus nerve capture that causes the laryngeal nerve tovibrate. Various embodiments use lead impedance to check for coughinduced by vagus nerve stimulation. Some embodiments performimpedance-based measurements of laryngeal vibrations without anyadditional hardware than that which is used by the neurostimulationsystem.

A vagus nerve capture threshold can be set by first recruiting A fibersthat cause laryngeal vibrations, and then increasing the intensity untila cough side effect is detected. The intensity is set between theintensity that caused the laryngeal vibrations and the intensity thatcaused the cough. For example, if the amplitude of the stimulationsignal is increased to increase the VST intensity and if 1 mA causedlaryngeal vibrations and 2.5 mA caused a cough, then the pacingamplitude may be set to 2.1 to 2.4 mA. However, determination ofthresholds by a physician is time consuming because of the multiplestimulating vectors that are possible. Some embodiments of the presentsubject matter use a device/lead based impedance sensor to measureimpedance changes caused by laryngeal vibrations and cough to guide thetherapy threshold programming. Different versions of an algorithm can beused to provide short term feedback during surgery or to providerelatively long follow-up monitoring.

FIG. 3 illustrates increasing VST intensity from the left side to theright side of the figure, and further illustrates that a VST intensitylevel can be set using the intensity threshold that elicits aphysiological response to the VST. For example, if laryngeal vibrationsare observed at VST intensity level “X”, the therapeutically-effectiveintensity level for the VST can be set as a percentage of “X” (e.g.approximately 75% of “X” or approximately 125% of “X”) or as an offset“Z” from “X” (e.g. “X” less “Z” or “X” plus “Z”). As generallyillustrated in FIG. 4, the intensity threshold that elicits aphysiological response can be used to set upper and lower limits for arange of VST intensities. An ability of the device to adjust the VSTintensity range may be limited based on the detected physiologicalresponse (e.g. laryngeal vibrations) to the VST. For example, a devicemay limit adjustments to the VST intensity to Y1% to Y2% of “X” (e.g.50% to 150% of the laryngeal vibration intensity). By way of example,the lower range may be below and the upper range above 100% of “X”, thelower and upper ranges may both be below 100% of “X”, or may both beabove 100% of “X”. Alternatively, offsets (“Z1” and/or “Z2” from “X”(not shown)) may be used for at least one of the beginning of theallowable range of intensities or the end of the allowable range ofintensities.

FIG. 5 illustrates increasing VST intensity from the left side to theright side of the figure, and further illustrates the intensitythreshold that elicits a physiological response to the VST that is usedto set the VST intensity. For example, if cough is observed thetherapeutically-effective intensity level for the VST can be set as apercentage, and offset, or other function of the VST intensity thatelicited the cough. As generally illustrated in FIG. 6, an ability ofthe device to adjust the VST intensity range may be limited based on thedetected cough response to VST. For example, a device may limitadjustments to the VST intensity to a range of percentages or otherfunction of the VST intensity that caused the cough (“X”). By way ofexample, the lower range may be below and the upper range above 100% of“X”, the lower and upper boundaries for the range may both be below 100%of “X”, or may both be above 100% of “X”. It is currently that, for mosttherapies, both the lower and upper boundaries will be below 100% of“X”.

FIG. 7 illustrates an embodiment, by way of example and not limitation,of an implantable medical device 100 capable of measuring impedance witha device housing or can 101 and a lead 102 extending from the can. Thelead includes multiples poles that can be used in a unipolarconfiguration or bipolar configuration. The laryngeal vibrations causethe lead and tissue to move with respect to each other, causing thecontact between the tissue and the poles to vary and thus causing theimpedance to vary. Some poles on the lead can be used to pace, and someembodiments monitor impedance using the poles that are used for pacing.In some embodiments, other poles (other than those used to pace) on themulti-polar lead can be used. In some embodiments, the drive current forthe impedance measuring is the neurostimulation current. In someembodiments, a dedicated, sub-therapeutic current is used as the drivecurrent for the impedance measurement. Both AC and DC coupled impedancecan be used. Some embodiments use multiple impedance vectors andphase-coherent detection. The impedance sensor can be used incombination with other sensors (accelerometer, strain gauge) and/orpatient/physician feedback.

The lead may be an intravascular lead configured to be fed into positionthrough the vasculature of the patient. The lead may be a subcutaneouslead. The lead may be inside or outside the carotid sheath, to provideelectrode(s) either adjacent to or surrounding the vagus nerve. Theillustrated lead includes four electrodes 103, 104, 105 and 106.However, the present subject matter is not limited to a particularnumber of electrodes. The can 101 may function as an electrode. In someembodiments, more than one electrode may be on the can 101. Variouscombinations of the lead electrodes and the can provide various vectorsthat can be used to calculate impedance between or among these variouscombinations. Laryngeal vibrations or cough affects the electrode-tissuecontact, which affects impedance. Thus, the present subject matter usesimpedance as a way to detect laryngeal vibrations and cough. Neuralstimulation may be delivered to a nerve, such as the vagus nerve, usingat least one of the electrodes on the lead. The current from the neuralstimulation may be used to detect the impedance, according to someembodiments. In some embodiments, a dedicated current is used to detectimpedance.

Titration, as used herein, refers to the process of adjusting the doseof the stimulation, ultimately to a level that is therapeutically orprophylactically effective. The dose includes an amount or intensity ofthe neural stimulation at a given time frame, and also includes thenumber of times the neural stimulation is delivered over a period oftime. The intensity of the neural stimulation may be adjusted byadjusting parameters such as amplitude, duty cycle, duration, and orfrequency of the neural stimulation, or the number of neural stimulationevents that occur over a period of time. FIG. 8 illustrates arepresentation of intermittent neural stimulation (INS). The figurediagrammatically shows the time-course of a neural stimulation thatalternates between intervals of stimulation being ON, when onestimulation pulse or a set of grouped stimulation pulses (i.e., a burst115) is delivered, and intervals of stimulation being OFF, when nostimulation pulses are delivered. Thus, for example, some embodimentsdeliver a plurality of monophasic or biphasic pulses within a neuralstimulation burst illustrated in FIG. 8. Pulses delivered within a burst115 may be delivered at a pulse frequency. These pulses also have anamplitude. Both the pulse frequency and the pulse amplitude affect thedose of the neural stimulation therapy. The duration of the stimulationON interval is sometimes referred to as the stimulation duration orburst duration. The burst duration also affects the dose of the neuralstimulation therapy. The start of a stimulation ON interval is atemporal reference point NS Event. The time interval between successiveNS Events is the INS Interval, which is sometimes referred to as thestimulation period or burst period 116. The burst period 116 or thenumber of neural stimulation events that occur over a time period alsoaffect the dose of the neural stimulation. For an application of neuralstimulation to be intermittent, the stimulation duration (i.e., ONinterval) is less than the stimulation period (i.e., INS Interval) whenthe neural stimulation is being applied. The duration of the OFFintervals of INS are determined by the durations of the ON interval andthe INS Interval. The duration of the ON interval relative to the INSInterval (e.g., expressed as a ratio) is sometimes referred to as theduty cycle of the INS.

FIG. 9 illustrates a memory 117, according to various embodiments, thatincludes instructions 118, operable on by the stimulation controlcircuitry, for controlling an up-titration routine by progressivelystepping up through defined parameter sets (e.g. parameter set 1 throughparameter set N), where each set incrementally changes (increases ordecreases) the stimulation dose or intensity of the stimulation therapy.This memory may be illustrated as part of a therapy titration/adjustmentmodule 119 in FIG. 10. The memory may include a plurality of neuralstimulation parameter sets, where each set includes a unique combinationof parameter values for the neural stimulation and wherein each uniquecombination of parameter values is defined to provide neural stimulationtherapy at an intensity level. The instructions include instructions forstepping through the plurality of neural stimulation parameter setsaccording to a schedule to change (increase or decrease) the intensityof the therapy until the therapy is at the desired long term intensity.Various embodiments provide a neural stimulation routine thatautomatically finds the desirable combination of therapy parameters(e.g. amplitude, pulse width, duty cycle) that provides a desiredtherapy intensity level.

FIG. 10 illustrates an embodiment of a therapy titration module 119,which may also be referred to as a therapy adjustment module. Accordingto various embodiments, the stimulation control circuit is adapted toset or adjust any one or any combination of stimulation features 120.Examples of stimulation features include the amplitude, frequency,polarity and wave morphology of the stimulation signal. Examples of wavemorphology include a square wave, triangle wave, sinusoidal wave, andwaves with desired harmonic components to mimic naturally-occurringbaroreflex stimulation. Some embodiments of the stimulation outputcircuit are adapted to generate a stimulation signal with apredetermined amplitude, morphology, pulse width and polarity, and arefurther adapted to respond to a control signal from the controller tomodify at least one of the amplitude, wave morphology, pulse width andpolarity. Some embodiments of the neural stimulation circuitry areadapted to generate a stimulation signal with a predetermined frequency,and are further adapted to respond to a control signal from thecontroller to modify the frequency of the stimulation signal.

The therapy titration module 119, also referred to as a therapyadjustment module, can be programmed to change stimulation sites 121,such as changing the stimulation electrodes used for a neural target orchanging the neural targets for the neural stimulation. For example,different electrodes of a multi-electrode cuff can be used to stimulatea neural target. Examples of neural targets include the right and leftvagus nerves and branches thereof, baroreceptors, the carotid sinus, andthe carotid sinus nerve. Autonomic neural targets can include afferentpathways and efferent pathways and can include sympathetic andparasympathetic nerves. The stimulation can include stimulation tostimulate neural traffic or stimulation to inhibit neural traffic. Thus,stimulation to evoke a sympathetic response can involve sympatheticstimulation and/or parasympathetic inhibition; and stimulation to evokea parasympathetic response can involve parasympathetic stimulationand/or sympathetic inhibition.

The therapy titration module 119 can be programmed to change stimulationvectors 122. Vectors can include stimulation vectors between electrodes,or stimulation vectors for transducers. For example, the stimulationvector between two electrodes can be reversed. One potential applicationfor reversing stimulation vectors includes changing from stimulatingneural activity at the neural target to inhibiting neural activity atthe neural target. More complicated combinations of electrodes can beused to provide more potential stimulation vectors between or amongelectrodes, One potential stimulation vector application involvesselective neural stimulation (e.g. selective stimulation of some axonsof the vagus nerve) or changing between a selective stimulation and amore general stimulation of a nerve trunk.

The therapy titration module 119 can be programmed to control the neuralstimulation according to stimulation instructions, such as a stimulationroutine or schedule 123, stored in memory. Neural stimulation can bedelivered in a stimulation burst, which is a train of stimulation pulsesat a predetermined frequency. Stimulation bursts can be characterized byburst durations and burst intervals. A burst duration is the length oftime that a burst lasts. A burst interval can be identified by the timebetween the start of successive bursts. A programmed pattern of burstscan include any combination of burst durations and burst intervals. Asimple burst pattern with one burst duration and burst interval cancontinue periodically for a programmed period or can follow a morecomplicated schedule. The programmed pattern of bursts can be morecomplicated, composed of multiple burst durations and burst intervalsequences. The programmed pattern of bursts can be characterized by aduty cycle, which refers to a repeating cycle of neural stimulation ONfor a fixed time and neural stimulation OFF for a fixed time. Duty cycleis specified by the ON time and the cycle time, and thus can have unitsof ON time/cycle time. According to some embodiments, the controlcircuit controls the neural stimulation generated by the stimulationcircuitry by initiating each pulse of the stimulation signal. In someembodiments, the stimulation control circuit initiates a stimulationsignal pulse train, where the stimulation signal responds to a commandfrom the controller circuitry by generating a train of pulses at apredetermined frequency and burst duration. The predetermined frequencyand burst duration of the pulse train can be programmable. The patternof pulses in the pulse train can be a simple burst pattern with oneburst duration and burst interval or can follow a more complicated burstpattern with multiple burst durations and burst intervals. In someembodiments, the stimulation control circuit controls the stimulationoutput circuit to initiate a neural stimulation session and to terminatethe neural stimulation session. The burst duration of the neuralstimulation session under the control of the control circuit can beprogrammable. The controller may also terminate a neural stimulationsession in response to an interrupt signal, such as may be generated byone or more sensed parameters or any other condition where it isdetermined to be desirable to stop neural stimulation.

A device may include a programmed therapy schedule or routine stored inmemory and may further include a clock or timer which can be used toexecute the programmable stimulation schedule. For example, a physiciancan program a daily/weekly schedule of therapy based on the time of day.A stimulation session can begin at a first programmed time, and can endat a second programmed time. Various embodiments initiate and/orterminate a stimulation session based on a signal triggered by a user.Various embodiments use sensed data to enable and/or disable astimulation session.

According to various embodiments, the stimulation schedule refers to thetime intervals or period when the neural stimulation therapy isdelivered. A schedule can be defined by a start time and an end time, ora start time and a duration. Various schedules deliver therapyperiodically. By way of example and not limitation, a device can beprogrammed with a therapy schedule to deliver therapy from midnight to 2AM every day, or to deliver therapy for one hour every six hours, or todeliver therapy for two hours per day, or according to a morecomplicated timetable. Various device embodiments apply the therapyaccording to the programmed schedule contingent on enabling conditions,such as sensed exercise periods, patient rest or sleep, a particularposition/posture, low heart rate levels, and the like. For example, thestimulation can be synchronized to the cardiac cycle based on detectedevents that enable the stimulation. The therapy schedule can alsospecify how the stimulation is delivered.

Some embodiments are configured to change a ramp-up time for increasingone or more stimulation parameters from OFF to a programmed intensity atthe start of the ON portion. Patients may tolerate higher stimulationlevels if there is not an abrupt change at the start of the duty cycle.The parameter increased during this ramp-up time may be amplitude, forexample, or other parameter or other combination of parameters thataffect the intensity of the stimulation.

FIG. 11 illustrates an embodiment of a routine that increases theintensity of the NCT therapy over a period of time. The intensity isincreased in increments 124. In the illustrated embodiments, a thresholddetermination routine 125 is performed to detect a lower boundaryphysiologic response to the neural stimulation such as a laryngealvibration response. In various embodiments, a cough detection routine126 or other side effect detection routine is performed to detect anupper boundary physiologic response to the neural stimulation. Someembodiments decrease the intensity of the NCT therapy over a period oftime to detect the physiologic responses (e.g. lower and/or upperboundaries) to the neural stimulation.

The present subject matter senses physiological responses using animpedance sensor configured to sense impedance changes caused by thephysiological response to the neural stimulation. As a specific example,some embodiments sense changes in impedance characteristics caused bylaryngeal vibrations, and some embodiments sense changes in impedancecharacteristics caused by cough. By way of example and not limitation,the laryngeal vibrations and cough can be used to determine lower andupper boundaries for the NCT. The impedance is sensed a plurality oftimes to provide a plurality of sensed impedance values. A plurality ofthe sensed impedance values is analyzed to confirm the laryngealvibrations. Some embodiments position the impedance sensorextravascularly in or proximate to the carotid sheath in a position toallow the sensor to sense changes in impedance characteristics caused bylaryngeal vibrations. Some embodiments position the impedance sensorintravascularly in or proximate to the carotid sheath to allow thesensor to sense changes in impedance characteristics caused by laryngealvibrations.

FIG. 12A illustrates, by way of example, impedance measurements. Theillustrated figure represents a baseline, an area with an increased meanand variability representing laryngeal vibrations, and an area with afurther increase in the mean and variability representing cough.Discrimination algorithms can be used to detect laryngeal vibrations andcough from the sensed impedance values. Some embodiments providediscrimination algorithms to detect muscle stimulation. Large musclestimulation is expected to look similar to cough.

FIG. 12B illustrates both raw and filtered impedance measurements when apatient is tapped close to the impedance sensor and when the patient istapped further away from the impedance sensor. Similar to FIG. 12A, avariability measure of the impedance values will indicate the presenceof laryngeal vibrations and cough. The first step change in impedancevariability will reflect the presence of laryngeal vibrations (comparedto baseline) and the second step change (if present) may reflect thepresence of cough or muscle stimulation (compared to laryngealvibrations). The figure indicates that the variability measure dependson the location of the sensor relative to the origin of the laryngealvibrations.

Various embodiments analyze a plurality of sensed impedance values todetect physiological responses to the NCT, such as laryngeal vibrationsand/or cough. Some embodiments correlate the timing of the neuralstimulation bursts to the timing of the physiological responses todetermine whether the physiological response is attributable to the NCT.According to various embodiments, the physiological response is detectedby detecting a change in impedance characteristics (e.g. detecting achange in absolute impedance values, detecting a change in a mean of thesensed impedance values, and/or detecting a change in variability of thesensed impedance values). FIG. 14 illustrates a step up in thevariability of the sensed impedance when laryngeal vibrations occur.FIG. 15 illustrates a step up in the variability of the sensed impedancewhen cough occurs. By way of example and not limitation, some systemembodiments monitor a trend of the variability of the sensed impedanceas the intensity is increased and detects the physiological response ifthe trend changes by more than threshold.

FIG. 13A illustrates the frequency transformation of the vagalstimulation pulses delivered at 160 beats per minute where the two peaksin frequencies are at 2.6 and 5.2 Hz respectively. The 5.2 Hz frequencypeak represents the second harmonic of 2.6 Hz. FIG. 13 B illustrates thefrequency transformation of the impedance signal collected during thevagal stimulation where the two primary peaks are again at 2.6 Hz and5.2 Hz, thus verifying capture by corresponding to the peak frequenciesof the vagal stimulation pulses. Thus, some embodiments performfrequency analysis on the stimulation and on the sensed impedance todetermine if the sensed impedance is affected by the stimulation. If thesensed impedance has a frequency response that compares favorably (e.g.peak-to-peak comparison) to the frequency response of the stimulation,then it can be concluded that the stimulation is affecting the impedanceresponse. Thus, the frequency analysis indicates capture. Variousembodiments incorporate the impedance sensor in the lead and/or the can.Some embodiments incorporate the impedance sensor into the lead or othertemporary guide catheters for use during implant. Some embodiments useimpedance sensor(s) with other sensors such as a pressure sensor and/oraccelerometer, and/or use patient or physician feedback.

Various embodiments of the present subject matter provide a programmedprocess used during implant. A baseline measure of impedance is obtainedwith multiple vectors, and the stimulation is delivered with theintensity of the stimulation increased in steps. Some embodimentsdecrease the intensity of the stimulation in steps. The stimulation isdelivered for a known time period at each setting. Impedancemeasurements are made for each pre-set time window. Some embodiments usephase-coherent detection to provide frequency filtering. The impedancemeasurements are analyzed. Some embodiments calculate a measure ofimpedance measurement variability. Examples of methods that may be usedinclude calculating standard deviation, a range, Or an Inter-PercentileRange such as an Inter Quartile Range (IQR). Some embodiments calculatea measure of impedance measurement average. Examples of methods that maybe used include calculating a mean or a median. The first step change isdetermined to be the start of laryngeal vibrations. The intensity wherelaryngeal vibrations start is used in a function to provide a thresholdand set the stimulation intensity. Lead re-positioning is recommended ifthe threshold is high. The determined stimulation threshold is recorded.

Various embodiments of the present subject matter provide a programmedprocess used during a follow up. The impedance sensor is used to obtaina baseline measure, and the stimulation is delivered with the intensityof the stimulation increased in steps. The stimulation is delivered fora known time period at each setting. Impedance measurements are made foreach pre-set time window. Some embodiments use phase-coherent detectionto provide frequency filtering. Some embodiments use the change inimpedance characteristics after the delivery of the VST pulse and lookin a certain time window after the delivery of the VST pulse. Typicallythe laryngeal vibrations occur after a short time interval (˜10 ms)after the delivery of the VST in the cervical region. Thus we would lookfor changes in impedance characteristics, after the delivery of each VSTpulse, following a certain time window. The impedance measurements areanalyzed. Some embodiments calculate a measure of impedance measurementvariability. Examples of methods that may be used include calculatingstandard deviation, a range, or an Inter-Percentile Range such as anInter Quartile Range (IQR). Some embodiments calculate a measure ofimpedance measurement average. Examples of methods that may be usedinclude calculating a mean or a median. The first step change isdetermined to be the start of laryngeal vibrations. The intensity wherelaryngeal vibrations start is used in a function to provide a threshold.For example, if laryngeal vibrations are sensed at 1 MA, the intensitythreshold can be set to 2 mA. A second step change can be used to detectcough. For example, if cough occurs at 3.2 mA, the threshold can be setat 3 mA. If the threshold is too high during implant or follow-up, leadre-positioning, both physical repositioning and electronicrepositioning, may be recommended. Some embodiments perform an automaticstimulation threshold determination and an automatic stimulation captureconfirmation. Some embodiments perform the automatic routine on abeat-to-beat basis, e.g., performing that after each stimulus. Someembodiments perform periodic follow-up of thresholds to monitor forlead/electrode migration, lead/electrode status, monitoring of healing.Some embodiments temporarily turn off the NCT or reduce the intensity ofthe NCT if a string of coughing is detected.

Various embodiments of the present subject matter provide a programmedprocess used for therapy verification. Laryngeal vibration capture ischecked intermittently such as, by way of example and not limitation,using a programmed schedule or periodically checked every 6 hours, 12hours, daily, weekly. Some embodiments check laryngeal vibration captureon demand. For example, users may manually request a check for laryngealvibration capture. Each time laryngeal vibration capture is checked, aplurality of impedance values are sensed and analyzed. The presence orabsence of laryngeal vibrations is logged and tracked. A therapy settingis modified if capture is continuously absent. If the highest settingdoes not cause laryngeal vibrations, a notification is sent or an alertissued. If capture is periodically present, a histogram can be generatedto convey how many measurements, or a percentage of measurements, wherecapture was present along with time-stamps. A message, such as “Therapywas delivered 50% of the time”, can be displayed or otherwisecommunicated.

FIG. 16 illustrates a VST system, according to various embodiments. Animplantable device may provide the entire VST system. Some embodimentsuse external devices to provide the monitoring functions, such as duringimplantation of an implantable vagus nerve stimulator. Some embodimentsuse implanted leads and external stimulators. The illustrated VST system127 includes a pulse generator 128 to provide VST, a modulator 129 tochange or modulate intensity of the VST, and a VST response monitor 130to provide feedback. The autonomic nervous system is generallyillustrated at 131. Appropriate electrode(s) 132 are used to providedesired neural stimulation and sensor(s) 133 to sense a parameter thatis affected by the neural stimulation. Physiological parameter(s) thatquickly respond to VST can be used in closed loop systems or during theimplantation process. Examples of such parameters include heart rate,laryngeal vibrations, blood pressure, respiration, and electrogramparameters. The present subject uses an impedance sensor to detectlaryngeal vibrations or cough caused by NCT. Other cardiovascularparameter(s) and other surrogate parameters that have a quick andpredictable response indicative of the overall response of theparasympathetic nervous system to the neural stimulation can be used.Other parameter(s) that have a slower response may be used to confirmthat a therapeutically-effective dose is being delivered. The sensor(s)and electrode(s) can be integrated on a single lead or can use multipleleads. Additionally, various system embodiments implement the functionsusing an implantable neural stimulator capable of communicating with adistinct or integrated implantable cardiac rhythm management device.

The illustrated response monitor 130 monitors the parameter during atime with stimulation to provide a first feedback signal 134 indicativeof a parameter value corresponding to a time with stimulation and duringa time without stimulation to provide a second feedback signal 135indicative of a parameter value corresponding to a time withoutstimulation. The signals 134 and 135 are illustrated as separate lines.These signals 134 and 135 can be sent over different signal paths orover the same signal path. A comparator 136 receives the first andsecond feedback signals 134 and 135 and determines a detected change inthe parameter value based on these signals. Additionally, the comparatorcompares the detected change with an allowed change, which can beprogrammed into the device. For example, the device can be programmed toallow a heart rate reduction during VST to be no less than a percentage(e.g. on the order of 95%) of heart rate without stimulation. The devicemay be programmed with a quantitative value to allow a heart ratereduction during VST to be no less than that quantitative value (e.g. 5beats per minute) than heart rate without stimulation. A comparison ofthe detected change (based on signals 134 and 135) and the allowedchange provide a comparison result 141, which is used to appropriatelycontrol the modulator to adjust the applied VST.

The illustrated device includes an impedance sensor 137 and an impedanceanalyzer 138 such as, by way of example and not limitation, an impedancevariability analyzer or frequency analyzer. The analyzer analyzes aplurality of sensed impedance values to determine if the laryngealvibrations and/or cough is caused by the neural stimulation. The deviceis programmed with an upper boundary value 140 such as may represent acough and a lower boundary 139 such as may represent laryngealvibrations. The output of the impedance analyzer 138 is compared to thelower and upper boundaries to determine if the VST intensity is out ofbounds.

Some embodiments use a therapy protocol that adjusts the VST intensity,limited by the upper boundary for the VST intensity and in someembodiments by the lower boundary for the VST intensity. The VSTintensity can be adjusted, within the allowed bounds set by the presentsubject matter, based on other parameters such as blood pressure,respiration, and electrogram measurement. Sonic therapy protocols adjustthe upper boundary and/or lower boundary for VST intensity based on aschedule (e.g. time of day) or sensed data (e.g. activity).

Various modulator embodiments adjust VST intensity by changing anamplitude of a stimulation signal used to provide VST, by changing afrequency of a stimulation signal used to provide VST, by changing aburst frequency of a stimulation signal used to provide VST, by changinga pulse width of a stimulation signal used to provide VST, by changing aduty cycle of a stimulation signal used to provide VST, or variouscombinations of two or more of these stimulation signal characteristics.

The illustrated system for delivering VST is useful in extended therapyapplications. Examples of extended therapy applications involve applyingstimulation to prevent remodeling of cardiac tissue and to reverseremodel cardiac tissue in cardiovascular disease. VST can be applied fora portion (approximately 10 seconds) of each minute, for example. A VSTdose may be adjusted by adjusting the duration or duty cycle of thestimulation (e.g. approximately 5 seconds or 15 seconds each minute orapproximately 5 to 15 seconds every 30 seconds or approximately 5 to 30seconds every 2 minutes, or approximately 5 seconds to 3 minutes every 5minutes or a continuous stimulation). According to an embodiment, theVST non-selectively stimulates both efferent and afferent axons. Theillustrated values are provided by way of example, and not limitation.Over the course of days, weeks, months and years, the physiologicalresponse to VST can vary for a number of reasons, such as nerveadaptation, tissue encapsulation, fibrosis, impedance changes, and thelike. Various closed loop system embodiments monitor at least oneparameter that has a quick and predictable response to VST, and uses themonitored parameter to appropriately change the neural stimulationsignal to result in a desired stimulation of the parasympathetic nervoussystem. Some embodiments monitor heart rate. Some embodiments monitorlaryngeal vibrations, and adjust VST intensity as necessary for the VSTto elicit laryngeal vibrations.

Open loop VST systems set the VST intensity to avoid or reduce heartrate effects of VST. For an open loop VST system, heart rate ismonitored during VST testing. This VST testing may be based on arelatively large human population to determine the heart rate threshold.The VST testing may also be performed during the implantation procedure,using a process that verifies capture of the vagus nerve using observedheart rate reduction, that determines the intensity threshold at whichthe heart rate reduction is observed, and that uses the intensitythreshold to provide an upper boundary or otherwise set the VSTintensity below the heart rate threshold. According to some embodiments,a lower boundary for the VST intensity can be set during theimplantation process. For example, laryngeal vibrations are felt by thepatient or sensed by a sensor such as an accelerometer at a VSTintensity level below the VST intensity level where a heart rate effectis detected. A combination of parameter settings is chosen to avoid anysignificant bradycardia effects. Some embodiments avoid any bradycardiaeffects. Some embodiments allow a relatively insignificant amount ofheart rate slowing (e.g. heart rate during VST at 95% of heart ratewithout VST). The upper boundary for the VST intensity is based on theallowed heart rate change caused by VST from the intrinsic heart ratewithout VST.

FIG. 17 illustrates an implantable medical device (IMD) 142 having aneural stimulation (NS) component 143 and a cardiac rhythm management(CRM) component 144 according to various embodiments of the presentsubject matter. The illustrated device includes a controller and memory.According to various embodiments, the controller includes hardware,software, or a combination of hardware and software to perform theneural stimulation and CRM functions. For example, the programmedtherapy applications discussed in this disclosure are capable of beingstored as computer-readable instructions embodied in memory and executedby a processor. For example, therapy schedule(s), programmableparameters and threshold detection or dose setting algorithms such asdisclosed herein can be stored in memory. Additionally, some embodimentsstore a threshold detection routine for detecting a threshold for theneural stimulation, and some embodiments store a dose setting routinefor titrating the dose. According to various embodiments, the controllerincludes a processor to execute instructions embedded in memory toperform the neural stimulation and CRM functions. The illustrated neuralstimulation therapy 145 can include VST, such as VST to treat heartfailure or other cardiovascular disease. Various embodiments include CRMtherapies 146, such as bradycardia pacing, anti-tachycardia therapiessuch as ATP, defibrillation and cardioversion, and cardiacresynchronization therapy (CRT). The illustrated device further includesa transceiver 147 and associated circuitry for use to communicate with aprogrammer or another external or internal device. Various embodimentsinclude a telemetry coil.

The CRM therapy component 144 includes components, under the control ofthe controller, to stimulate a heart and/or sense cardiac signals usingone or more electrodes. The illustrated CRM therapy section includes apulse generator 148 for use to provide an electrical signal through anelectrode to stimulate a heart, and further includes sense circuitry 149to detect and process sensed cardiac signals. An interface 150 isgenerally illustrated for use to communicate between the controller 143and the pulse generator 148 and sense circuitry 149. Three electrodesare illustrated as an example for use to provide CRM therapy. However,the present subject matter is not limited to a particular number ofelectrode sites. Each electrode may include its own pulse generator andsense circuitry. However, the present subject matter is not so limited.The pulse generating and sensing functions can be multiplexed tofunction with multiple electrodes.

The NS therapy component 143 includes components, under the control ofthe controller, to stimulate a neural stimulation target and/or senseparameters associated with nerve activity or surrogates of nerveactivity such as heart rate, blood pressure, respiration. Threeinterfaces 151 are illustrated for use to provide neural stimulation.However, the present subject matter is not limited to a particularnumber interfaces, or to any particular stimulating or sensingfunctions. Pulse generators 152 are used to provide electrical pulses totransducer/electrode or transducers/electrodes for use to stimulate aneural stimulation target. According to various embodiments, the pulsegenerator includes circuitry to set, and in some embodiments change, theamplitude of the stimulation pulse, the pulse width of the stimulationpulse, the frequency of the stimulation pulse, the burst frequency ofthe pulse, and the morphology of the pulse such as a square wave,triangle wave, sinusoidal wave, and waves with desired harmoniccomponents to mimic white noise or other signals. Sense circuits 153 areused to detect and process signals from a sensor, such as a sensor ofnerve activity, heart rate, blood pressure, respiration, and the like.Sensor(s) may be used to sense laryngeal vibrations. Sensor(s) may beused to detect a state (e.g. accelerometer used to detect activity). Theinterfaces 151 are generally illustrated for use to communicate betweenthe controller 143 and the pulse generator 152 and sense circuitry 153.Each interface, for example, may be used to control a separate lead.Various embodiments of the NS therapy section only include a pulsegenerator to stimulate a neural target. The illustrated device furtherincludes a clock/timer 154, which can be used to deliver the programmedtherapy according to a programmed stimulation protocol and/or schedule.

FIG. 18 shows a system diagram of an embodiment of amicroprocessor-based implantable device, according to variousembodiments. The controller of the device is a microprocessor 155 whichcommunicates with a memory 156 via a bidirectional data bus. Thecontroller could be implemented by other types of logic circuitry (e.g.,discrete components or programmable logic arrays) using a state machinetype of design. As used herein, the term “circuitry” should be taken torefer to either discrete logic circuitry or to the programming of amicroprocessor. Shown in the figure are three examples of sensing andpacing channels designated “A” through “C” comprising bipolar leads withring electrodes 157A-C and tip electrodes 158A-C, sensing amplifiers159A-C, pacing stimuli 160A-C, and channel interfaces 161A-C. Eachchannel thus includes a pacing channel made up of the pulse generatorconnected to the electrode and a sensing channel made up of the senseamplifier connected to the electrode. The channel interfaces 161A-Ccommunicate bidirectionally with the microprocessor 155, and eachinterface may include analog-to-digital converters for digitizingsensing signal inputs from the sensing amplifiers and registers that canbe written to by the microprocessor in order to output pacing pulses,change the pacing pulse amplitude, and adjust the gain and thresholdvalues for the sensing amplifiers. The sensing circuitry of thepacemaker detects a chamber sense, either an atrial sense or ventricularsense, when an electrogram signal (i.e., a voltage sensed by anelectrode representing cardiac electrical activity) generated by aparticular channel exceeds a specified detection threshold. Pacingalgorithms used in particular pacing modes employ such senses to triggeror inhibit pacing. The intrinsic atrial and/or ventricular rates can bemeasured by measuring the time intervals between atrial and ventricularsenses, respectively, and used to detect atrial and ventriculartachyarrhythmias.

The electrodes of each bipolar lead are connected via conductors withinthe lead to a switching network 162 controlled by the microprocessor.The switching network is used to switch the electrodes to the input of asense amplifier in order to detect intrinsic cardiac activity and to theoutput of a pulse generator in order to deliver a pacing pulse. Theswitching network also enables the device to sense or pace either in abipolar mode using both the ring and tip electrodes of a lead or in aunipolar mode using only one of the electrodes of the lead with thedevice housing (can) 163 or au electrode on another lead serving as aground electrode. A shock pulse generator 164 is also interfaced to thecontroller for delivering a defibrillation shock via shock electrodes(e.g. electrodes 165 and 166) to the atria or ventricles upon detectionof a shockable tachyarrhythmia.

Neural stimulation channels, identified as channels D and E, areincorporated into the device for delivering parasympathetic stimulationand/or sympathetic inhibition, where one channel includes a bipolar leadwith a first electrode 167D and a second electrode 168D, a pacingstimulus 169D, and a channel interface 170D, and the other channelincludes a bipolar lead with a first electrode 167E and a secondelectrode 168E, a pacing stimulus 169E, and a channel interface 170E.Other embodiments may use unipolar leads in which case the neuralstimulation pulses are referenced to the can or another electrode. Otherembodiments may use tripolar or multipolar leads. In variousembodiments, the pulse generator for each channel outputs a train ofneural stimulation pulses which may be varied by the controller as toamplitude, frequency, duty-cycle, and the like. In this embodiment, eachof the neural stimulation channels uses a lead which can beintravascularly disposed near an appropriate neural target. Other typesof leads and/or electrodes may also be employed. A nerve cuff electrodemay be used in place of an intravascularly disposed electrode to provideneural stimulation. In some embodiments, the leads of the neuralstimulation electrodes are replaced by wireless links. Sensor(s) 171 areused by the microprocessor to determine capture (e.g. laryngealvibrations), the efficacy of therapy (e.g. heart rate, blood pressure)and/or detect events (e.g. cough) or states (e.g. activity sensors).

The figure illustrates a telemetry interface 172 connected to themicroprocessor, which can be used to communicate with an externaldevice. The illustrated microprocessor is capable of performing neuralstimulation therapy routines and myocardial (CRM) stimulation routines.Examples of NS therapy routines include VST therapies to providemyocardial therapies. NS therapy routines also include routines oralgorithms as described in this document. Examples of myocardial therapyroutines include bradycardia pacing therapies, anti-tachycardia shocktherapies such as cardioversion or defibrillation therapies,anti-tachycardia pacing therapies (ATP), and cardiac resynchronizationtherapies (CRT).

FIGS. 19-20 illustrate system embodiments adapted to provide VST, andare illustrated as bilateral systems that can stimulate both the leftand right vagus nerve. Those of ordinary skill in the art willunderstand, upon reading and comprehending this disclosure, that systemscan be designed to stimulate only the right vagus nerve, systems can bedesigned to stimulate only the left vagus nerve, and systems can bedesigned to bilaterally stimulate both the right and left vagus nerves.The systems can be designed to stimulate nerve traffic (providing aparasympathetic response when the vagus is stimulated), or to inhibitnerve traffic (providing a sympathetic response when the vagus isinhibited). Various embodiments deliver unidirectional stimulation orselective stimulation of some of the nerve fibers in the nerve. FIGS.19-20 illustrate the use of a lead to stimulate the vagus nerve.Wireless technology could be substituted for the leads, such that aleadless electrode is adapted to stimulate a vagus nerve and is furtheradapted to wirelessly communicate with an implantable system for use incontrolling the VST.

FIG. 19 illustrates a system embodiment in which an IMD 173 is placedsubcutaneously or submuscularly in a patient's chest with lead(s) 174positioned to stimulate a vagus nerve. According to various embodiments,neural stimulation lead(s) 174 are subcutaneously tunneled to a neuraltarget, and can have a nerve cuff electrode to stimulate the neuraltarget. Some vagus nerve stimulation lead embodiments areintravascularly fed into a vessel proximate to the neural target, anduse electrode(s) within the vessel to transvascularly stimulate theneural target. For example, some embodiments stimulate the vagus usingelectrode(s) positioned within the internal jugular vein. Otherembodiments deliver neural stimulation to the neural target from withinthe trachea, the laryngeal branches of the internal jugular vein, andthe subclavian vein. The neural targets can be stimulated using otherenergy waveforms, such as ultrasound and light energy waveforms. Theillustrated system includes leadless ECG electrodes 175 on the housingof the device. These ECG electrodes are capable of being used to detectheart rate, for example.

FIG. 20 illustrates an IMD 176 placed subcutaneously or submuscularly ina patient's chest with lead(s) 177 positioned to provide a CRM therapyto a heart, and with lead(s) 178 positioned to stimulate and/or inhibitneural traffic at a neural target, such as a vagus nerve, according tovarious embodiments. According to various embodiments, neuralstimulation lead(s) are subcutaneously tunneled to a neural target, andcan have a nerve cuff electrode to stimulate the neural target. Somelead embodiments are intravascularly fed into a vessel proximate to theneural target, and use transducer(s) within the vessel totransvascularly stimulate the neural target. For example, someembodiments target the vagus nerve using electrode(s) positioned withinthe internal jugular vein.

FIG. 21 is a block diagram illustrating an embodiment of an externalsystem 179. The external system includes a programmer, in someembodiments. In the illustrated embodiment, the external system includesa patient management system. As illustrated, the external system is apatient management system including an external device 180, atelecommunication network 181, and a remote device 182. The externaldevice 180 is placed within the vicinity of an implantable medicaldevice (IMD) and includes an external telemetry system 183 tocommunicate with the IMD. The remote device(s) is in one or more remotelocations and communicates with the external device through the network,thus allowing a physician or other caregiver to monitor and treat apatient from a distant location and/or allowing access to varioustreatment resources from the one or more remote locations. Theillustrated remote device includes a user interface 184. According tovarious embodiments, the external device includes a neural stimulator, aprogrammer or other device such as a computer, a personal data assistantor phone. The external device, in various embodiments, includes twodevices adapted to communicate with each other over an appropriatecommunication channel, such as a computer by way of example and notlimitation. The external device can be used by the patient or physicianto provide feedback indicative of patient discomfort, for example.

As will be understood by one of ordinary skill in the art upon readingand comprehending the present subject matter, various embodiments of thepresent subject matter improve patient acceptance of therapy, maintainefficacious levels of therapy, allow patient flexibility in therapymanagement, and generally improve the quality of life of the patient whois receiving the NCT. The modules and other circuitry shown anddescribed herein can be implemented using software, hardware, firmwareand combinations thereof.

The above detailed description is intended to be illustrative, and notrestrictive. Other embodiments will be apparent to those of skill in theart upon reading and understanding the above description. The scope ofthe invention should, therefore, be determined with reference to theappended claims, along with the full scope of equivalents to which suchclaims are entitled.

1. A method, comprising: delivering a vagal stimulation therapy (VST) toa vagus nerve of a patient; detecting laryngeal vibrations to determinewhether the VST is capturing the vagus nerve, wherein detectinglaryngeal vibrations includes: sensing impedance in a cervical region ofa patient to sense changes in impedance characteristics caused bylaryngeal vibrations, wherein sensing impedance includes sensingimpedance a plurality of times to provide a plurality of sensedimpedance values; and analyzing a plurality of the sensed impedancevalues to confirm the laryngeal vibrations.
 2. The method of claim 1,wherein delivering the VST includes delivering the VST using anelectrode in a blood vessel; and sensing impedance includes sensingimpedance using the electrode in the blood vessel.
 3. The method ofclaim 2, wherein the blood vessel is an internal jugular vein.
 4. Themethod of claim 1, further comprising detecting whether the VST iscausing cough, including analyzing a plurality of the sensed impedancevalues to confirm the cough.
 5. The method of claim 1, whereindelivering VST includes delivering a neuro cardio therapy (NCT) to treata cardiovascular disease, wherein delivering NCT includes delivering NCTas a heart failure therapy or delivering NCT as a hypertension therapy.6. The method of claim 1, wherein analyzing the plurality of the sensedimpedance values includes detecting a change in absolute impedancevalues, detecting a change in mean of the sensed impedance values, ordetecting a change in variability of the sensed impedance values.
 7. Themethod of claim 6, wherein analyzing the plurality of the sensedimpedance values includes analyzing the variability of the plurality ofthe sensed impedance, and analyzing the variability of the plurality ofthe sensed impedance includes determining a standard deviation or anInter-Percentile Range of the sensed impedance.
 8. A method, comprising:performing a threshold determination routine for delivering a vagalstimulation therapy (VST) to a vagus nerve of a patient, whereinperforming the threshold determination routine includes: delivering VSTto the vagus nerve; changing an intensity of the VST in a plurality ofintensity steps; and at each intensity step, monitoring for laryngealvibrations, wherein monitoring for laryngeal vibrations includes:sensing impedance in a cervical region of a patient to sense changes inimpedance characteristics caused by laryngeal vibrations, whereinsensing impedance includes sensing impedance a plurality of times toprovide a plurality of sensed impedance values; and analyzing aplurality of the sensed impedance values to confirm the laryngealvibrations.
 9. The method of claim 8, wherein analyzing the plurality ofthe sensed impedance values includes detecting a change in absoluteimpedance values that indicates laryngeal vibrations, detecting a meanof the sensed impedance values that indicates laryngeal vibrations, ordetecting variability of the sensed impedance values that indicateslaryngeal vibrations.
 10. The method of claim 8, further comprising:delivering the VST at a VST intensity level; and intermittentlyperforming a threshold verification routine, including: sensingimpedance a plurality of times each time the threshold verificationroutine is performed to provide a plurality of sensed impedance values;analyzing the plurality of the sensed impedance values each time thethreshold verification routine is performed to confirm the laryngealvibrations at the VST intensity level; and recording a result of theanalysis.
 11. The method of claim 8, further comprising: delivering theVST at a VST intensity level; and intermittently performing a thresholdverification routine, including: sensing impedance a plurality of timeseach time the threshold verification routine is performed to provide aplurality of sensed impedance values; analyzing the plurality of thesensed impedance values each time the threshold verification routine isperformed to confirm the laryngeal vibrations at the VST intensitylevel; and notifying a patient or physician if laryngeal vibrations arenot confirmed at the VST intensity level.
 12. The method of claim 8,further comprising: delivering the VST at a VST intensity level; andintermittently performing a threshold verification routine, including:sensing impedance a plurality of times each time the thresholdverification routine is performed to provide a plurality of impedancevalues; analyzing the plurality of the sensed impedance values each timethe threshold verification routine is performed to confirm the laryngealvibrations at the VST intensity level; and if laryngeal vibrations arenot confirmed at the VST intensity level, performing the thresholdverification routine to identify an intensity step where laryngealvibrations are confirmed.
 13. The method of claim 8, comprisingperforming a cough detection routine for delivering VST after laryngealvibrations are found, wherein performing the cough detection routineincludes: sensing impedance to provide a plurality of sensed impedancevalues for each of a plurality of intensity steps higher than theintensity step at which laryngeal vibrations are found; and analyzingthe plurality of sensed impedance values for each of a plurality ofintensity steps higher than the intensity step at which laryngealvibrations are found, wherein a step increase in absolute value, mean orvariability of sensed impedance from a laryngeal vibration levelindicates cough.
 14. The method of claim 8, wherein analyzing theplurality of the sensed impedance values includes determining a standarddeviation or an Inter-Percentile Range of the variability of the sensedimpedance.
 15. A device for delivering vagal stimulation therapy (VST)to a vagus nerve of a patient, comprising: a neural stimulatorconfigured to deliver the VST to the vagus nerve in a cervical region ofthe patient; an implantable impedance sensor configured for use indetecting changes in impedance characteristics in a cervical region ofthe patient caused by laryngeal vibrations, wherein the impedance sensoris configured to generate sensed impedance values; and an impedanceanalyzer configured to analyze the sensed impedance values generated bythe sensor, wherein the analyzer is configured to detect laryngealvibrations or cough from the sensed impedance values.
 16. The device ofclaim 15, further comprising a controller configured to control anintensity of the VST delivered by the neural stimulator, and perform athreshold verification routine, wherein in performing the thresholdverification routine, the controller is configured to: change theintensity of the VST in a plurality of intensity steps; and monitor forlaryngeal vibrations at each intensity step, wherein in monitoring forlaryngeal vibrations, the controller is configured to: receive aplurality of sensed impedance values from the impedance sensor at eachintensity step; and analyze the plurality of sensed impedance values foreach intensity step to determine if the VST is causing laryngealvibrations.
 17. The device of claim 16, wherein the controller isconfigured to detect laryngeal vibrations from these sensed impedancevalues, configured to detect cough or muscle stimulation from thesesensed impedance values, and configured to adjust the intensity of theVST in response to an output from the impedance analyzer.
 18. The deviceof claim 15, wherein the controller is further configured to adjust theintensity of the VST in response to an output from the impedanceanalyzer.
 19. The device of claim 15, further comprising a controllerconfigured to control an intensity of the VST delivered by the neuralstimulator, and intermittently perform a threshold detection routine,wherein in performing the threshold detection routine, the controller isconfigured to: receive a plurality of sensed impedance values from theimpedance sensor each time the threshold verification routine isperformed; analyze the sensed impedance values each time the thresholdverification routine is performed to confirm the laryngeal vibrations atthe VST intensity level; and if laryngeal vibrations are not confirmedat the VST intensity level, perform the threshold verification routineto identify an intensity step where laryngeal vibrations are confirmed,or notify the patient or a physician if laryngeal vibration is notconfirmed at a highest VST intensity level that the device is configuredto deliver.
 20. The device of claim 15, wherein the implantableimpedance sensor includes: an electrode on a lead configured to beimplanted in a carotid sheath of the patient; or an electrode on a leadconfigured to be implanted in an internal jugular vein of the patient.21. The device of claim 19, wherein the neural stimulator is configuredto deliver VST to the vagus nerve from the internal jugular vein.
 22. Amethod for detecting laryngeal vibrations, comprising: sensing impedancein a cervical region of a patient to sense changes in impedancecharacteristics caused by laryngeal vibrations, wherein sensingimpedance includes sensing impedance a plurality of times to provide theplurality of sensed impedance values; and analyzing a plurality of thesensed impedance values to confirm the laryngeal vibrations, whereinsensing impedance includes: sensing impedance changes in or near acarotid sheath; or sensing impedance using a lead in an internal jugularvein.
 23. A method for detecting cough, comprising: sensing impedance ina cervical region of a patient to sense changes in impedancecharacteristics caused by cough, wherein sensing impedance includessensing impedance a plurality of times to provide a plurality of sensedimpedance values; and analyzing the plurality of the sensed impedancevalues to confirm the cough, wherein sensing impedance includes: sensingimpedance changes in or near a carotid sheath; or sensing impedanceusing a lead in an internal jugular vein.